One of the hallmark features of the brain is its enormous degree of plasticity, which is evident in the ability to learn and store information throughout lifetime. It is generally assumed that memory storage rests on changes in synaptic strength, such as long-term potentiation (LTP) and long-term depression (LTD). For example, Marr-Albus-Ito theories suggest that cerebellar motor learning is mediated by LTD at parallel fiber (PF) synapses onto Purkinje cells. PF-LTP might function as a reversal mechanism (Jvrntell and Hansel, 2006). "Synaptic memories" are optimally suited as cellular learning correlates, because they are experience-dependent and can be synapse-specific, allowing for selective information storage. However, over the last years it has become clear that synaptic plasticity is not the only player on the scene. Forms of intrinsic plasticity (alterations in neuronal excitability) have been described and might play a role in information storage as well (Hansel et al., 2001; Zhang and Linden, 2003; Frick and Johnston, 2005). But how does intrinsic plasticity interact with LTD and LTP, and what role does it play in learning and memory? We plan to address these questions in cerebellar Purkinje cells. A crucial advantage of the cerebellum in learning research is that the underlying circuitry is simple and well-characterized, which is helpful when studying the interaction of different types of plasticity in information storage (Hansel et al., 2001). Our preliminary data demonstrate an activity-dependent increase in Purkinje cell excitability, which depends on the activation of protein phosphatases (PP1/2A and PP2B) and is partially mediated by a down-regulation of SK-type calcium-sensitive K channels. We observed that the enhanced excitability upregulates spontaneous spike firing in Purkinje cells, which does not alter the tonic spike rate of the target DCN neurons, but lowers the impact of PF synapses onto Purkinje cells by reducing the signal-to-noise ratio. Here, we propose four specific aims to further characterize Purkinje cell intrinsic plasticity. First, we plan to examine the signaling cascades involved in the induction of excitability changes, including calcium signaling, phosphatases and kinases (including the use of mutant mice deficient in PKC, 1CaMKII and PP2B, respectively). Second, we plan to search for additional types of ion channels (next to SK channels) mediating the excitability enhancement. Third, we wish to examine whether this potentiation of Purkinje cell excitability subsequently alters calcium signaling in dendritic shafts and spines (using confocal microscopy) and affects the probabilities for LTD / LTP induction. Fourth, using a combination of somato-dendritic double-patching and calcium imaging, we plan to determine the spatial dimension of excitability changes. The suggested project is part of our long-term objective to reveal underlying mechanisms of (motor) learning and to develop novel modes for the treatment of motor learning deficits and memory disorders in general. To this end, we will also test genetically altered mice (SK channel transgenics and PP2B knock-outs) in behavioral learning tasks to study the role of intrinsic plasticity in cerebellar motor learning. PUBLIC HEALTH RELEVANCE it is widely believed that learning and memory are mediated by long-term alterations in the efficacy of synaptic transmission, such as long-term potentiation (LTP) and long-term depression (LTD). Abnormalities in the signaling cascades triggering LTP and LTD can cause learning deficits, such as in cerebellar ataxias, in which the fine-adjustment of motor coordination and motor learning are disturbed. Here, we suggest to characterize a novel type of non-synaptic plasticity, which is associated with an increase in the intrinsic membrane excitability of cerebellar Purkinje cells, and to describe its involvement in motor learning (and related cerebellar learning deficits). [unreadable] [unreadable] [unreadable]